Opiates are a highly addictive group of drugs that have a major potential for abuse. There is considerable interest in identifying the neural substrates of opiate abuse, and in elucidating the physiological processes that may contribute to drug dependency. Such information should also be useful in identifying more general underlying principles of drug dependency. Recent evidence has implicated the hippocampal formation as a site that can sustain self-administration of opioids. We intend to study the physiological consequences of activation of opioid receptors found in this region on synaptic transmission. A major emphasis will be placed on the study of the endogenously released opioid peptides. Our initial data suggest that opioids released from hippocampal mossy fiber synapses play a critical role in the formation of long-term synaptic potentiation (LTP). The mechanism of this interaction between opioids and LTP is novel, in that unlike other actions previously described, GABAergic disinhibition does not mediate this opioid effect. Further, the presence of naloxone during high frequency stimulation of mossy fibers reveals a novel depression of synaptic transmission similar to the phenomenon of long-term depression or LTD reported at other synapses in the hippocampus. We intend to further explore these findings using state-of-the-art electrophysiological techniques. We will test four hypotheses: 1) Endogenous opioids modulate mossy fiber synaptic transmission in a frequency dependent manner; 2) One specific receptor subtype mediates the effect of opioids; 3) Opioids facilitate LTP induction by increasing postsynaptic calcium flux; 4) Opioids facilitate LTP by acting at a presynaptic site. These experiments will yield important new data concerning the physiological actions of opioids in a brain structure that is not only well characterized anatomically, physiologically and biochemically, but which also may itself be a neural substrate for drug dependence.